Interaction of ibogaine analogs with the nicotinic acetylcholine receptor

Ibogaine analogs, especially 18-methoxycoronaridine (18-MC), bind to a specific site within the ion channel of the nicotinic acetylcholine receptor (AChR) when the receptor is in a desensitized state. The affinity of 18-MC for this site is about 0.17 μM in the desensitized state, much higher than in the resting state (12 μM). The binding site overlaps with the TCP locus, located between valine and leucine rings in the channel. These compounds enhance binding of the agonist cytisine only when the receptor is in a resting but activable state, not when desensitized. The findings suggest that ibogaine analogs inhibit the AChR by promoting receptor desensitization.

Study at a glance

Abstract

PURPOSE: Characterization of the binding sites for ibogaine analogs on the nicotinic acetylcholine receptor (AChR) in the resting and desensitized states. METHODS: [ 3 H]18‐methoxycoronaridine ([ 3 H]18‐MC) Scatchard‐plots using Torpedo AChR membranes, [ 3 H]TCP (a well characterized noncompetitive antagonist) competition binding experiments and Schild‐type analysis, analog‐induced binding modulation of the agonist [ 3 H]cytisine, and molecular modeling of the Torpedo AChR ion channel and molecular docking of 18‐MC. RESULTS: (1) there is one (0.86 ± 0.13) high‐affinity (K d = 0.23 ± 0.04 μM) binding site for [ 3 H]18‐MC in the desensitized AChR; (2) the affinity (in μM) of each 18‐MC congener for the [ 3 H]TCP locus in the desensitized state follows the sequence: 18‐MC (0.17 ± 0.01) > 2‐methoxyethyl‐18‐MC (1.3 ± 0.1) ~ 18‐methylaminocoronaridine (1.3 ± 0.2) > (+)coronaridine (3.2 ± 0.4) ~ albifloranine (3.2 ± 0.3) > ibogaine (5.4 ± 0.3). Whereas, the affinity sequence in the resting state is: 18‐MC (12 ± 1) > 18‐methylaminocoronaridine (20 ± 2) > (+)coronaridine (48 ± 5) > 2‐methoxyethyl‐18‐MC (82 ± 8) > ibogaine (182 ± 17) > albifloranine (252 ± 24); (3) Schild‐type analysis suggests that 18‐MC interacts with the TCP site in a steric manner; (4) [ 3 H]cytisine binding is enhanced by the 18‐MC congeners when the AChR is in the resting but activable state, but not in the desensitized state; and (5) 18‐MC interacts with a domain formed between valine (position 13’) and leucine (position 9’) rings. CONCLUSIONS: binding and modeling results indicate that the 18‐MC binding site overlaps the TCP locus located in the middle of the desensitized ion channel, and that ibogaine congeners may inhibit the AChR by inducing the desensitization process.